Daniel Cabaret

The synthesis and evaluation of benzofuranones as β-lactamase substrates

Abstract 6- and 7-Carboxy-3-phenylacetamido-3 H -1-benzofuran-2-one have been synthesized as potential β-lactamase substrates and/or inhibitors. These compounds were prepared by lactonization of the corresponding, appropriately substituted phenylglycines. The latter compounds were prepared by either the Strecker or the Bucherer–Berg method. The benzofuran-2-ones were less stable in aqueous solution than the analogous acyclic phenaceturate esters but comparably stable to analogous benzopyran-2-ones. They differed from the latter compounds however in that the C-3 hydrogen of the furan-2-ones, adjacent to the lactone carbonyl group, was distinctly acidic; 7-carboxy-3-phenylacetamido-3 H -1-benzofuran-2-one exists largely as an enolate at pH 7.5. The furan-2-ones were β-lactamase substrates with reactivity very similar to the analogous acyclic phenaceturates. They were not, however, dd -peptidase inhibitors and are thus unlikely to have antibiotic activity. The structural basis for these observations is discussed.

Synthesis and resolution of β2,2-HBin, the first enantiomerically stable β-amino acid with chirality only due to axial dissymmetry

Abstract The first gem -disubstituted β 2,2 -amino acid possessing only axial chirality, was synthesized by bis-alkylation of methyl or ethyl cyanoacetate with both racemic and enantiomerically pure ( R )-2,2′-bis-(bromomethyl)-1,1′-binaphthyl, followed by NaBH 4 /CoCl 2 reduction of the cyano group, treatment of the resulting amino esters with Boc 2 O and finally saponification of the ester function, to afford the C - and/or N -protected derivatives of 2′,1′:1,2;1′′,2′′:3,4-dinaphthcyclohepta-1,3-diene-6-aminomethyl-6-carboxylic acid: ( RS )- and ( R )-X-β 2,2 -HBin-OR (X=Boc; H) (R=Me, Et or H). For the medium-scale resolution of β 2,2 -HBin, the racemic amino esters ( RS )-H-β 2,2 -HBin-OR (R=Me, Et) were treated with benzoic anhydride and the resulting derivatives ( RS )-Bz-β 2,2 -HBin-OR were saponified. The obtained ( RS )-Bz-β 2,2 -HBin-OH was coupled with l -phenylalanine cyclohexylamide by the EDC/HOBt method to afford the dipeptide diastereoisomers Bz-( R )-Bin- l -Phe-NH-C 6 H 11 and Bz-( S )-Bin- l -Phe-NH-C 6 H 11 , which were separated by chromatography. Complete hydrolysis under acidic conditions, followed by esterification of the resulting free amino acid enantiomers, N -protection and saponification, led to the enantiomerically pure derivatives ( R )- and ( S )-X-β 2,2 -HBin-OR (X=Boc; H) (R=Me, H).

Organomagnesien reactif reducteur : VI. Comparaison de la stereochimie de la reduction des cetones et des composes a double liaison ethylenique activee par les organomagnesiens chiraux

Abstract The reduction of alkylidene cyanoacetic esters (Z- and E-ethyl 2-cyano-3-phenyl butenates) and the corresponding ketone (acetophenone) by chiral organomagnesium halides gives opposite stereoselectivities. These results are rationalized by the previously proposed cyclic mechanism of Whitmore for the ketone reduction and by a non-cyclic mechanism with polar orientation of the reagents in the reduction of the ethylenic compounds.

Surface enhanced enantiodifferentiation in reactions of chiral acetoacetates

Abstract The stereoselectivity of the alkylation of chiral acetoacetates by racemic secondary alkyl halides changes when the reaction is carried out on a solid support; the change can be interpreted in terms of a model involving surface imposed conformational restrictions.

Etude stereochimique de l'alkylation d'anions par des derives p-nitrobenzyliques optiquement actifs : Competition SN2-SNR1

Abstract Competition between S RN 1,S N 2 and S RN 1 mechanisms is discussed according to the stereochemical results in the alkylation of anions by optically active secondary p -nitrobenzyl reagents. Results from alkylation of the anions of benzylcyanide C and α-aminonitrile A by p -nitrobenzyl chloride 2 rule out S N 2 and S RN 2 mechanisms. On the other hand, the S N 2 process becomes exclusive in O -and C -alkylation of the acetoacetic ester anion B by the p -nitrobenzyl phosphonium salt, and this result shows that it is possible to obtain p -nitrobenzyl alkylation products without racemisation. C -Alkylation of the anion B by halide 2 involves an S N 2-electron transfer competition. The whole result illustrates that the stereochemical method provides precise information on the mechanism of these reactions.

A low-epimerizing peptide coupling reagent based on the rearrangement of a carboxylic-sulfonic mixed anhydride

Abstract A series of peptides has been prepared using an o -hydroxybenzenesulfonyl chloride as the condensation reagent. Experimentally, the coupling is a one pot two-steps reaction: formation and aminolysis of a substituted aryl ester. The first step occurs by an elimination-addition reaction involving a sulfoquinone intermediate, followed by an efficient six-membered acyl transfer reaction in the phenolic carboxylic-sulfonic mixed anhydride intermediate. The Young and Anteunis tests show that the degree of epimerization is very low in methylene chloride and acetonitrile.

Alkylation des esters acetylacetiques par des alcools chiraux, par deshydratation intermoleculaire. Correlation entre les puretes optiques des produits formes.

Abstract The formation of the C and O-alkylates involves inversion of configuration and the same weak racemization.

Organomagnesien reactif reducteur : V. Induction asymetrique dans la reduction des esters chiraux α-β ethyleniques☆

Abstract Prelogs rule, predicting the stereoselectivity of nucleophilic addition to the α-ketoesters of chiral alcohols, is also applicable to the reduction of α,β-ethylenic esters by LiAlH4, but this rule is no longer valid when organomagnesium halides are used as reducing agents. This difference between the two reactions is rationalized by the degree of complexation of the metallic ions of the two reducing agents in the transition states.

Substituted Aryl Malonamates as New Serine β-Lactamase Substrates: Structure-Activity Studies

A series of substituted aryl malonamates have been prepared. These compounds are analogues of aryl phenaceturates where the amido side chain has been replaced by a retro-amide. Like the phenaceturates, these compounds are substrates of typical class A and class C beta-lactamases, particularly of the latter, and of soluble DD-peptidases. The effect of substituents alpha to the ester carbonyl group on turnover by these enzymes is similar to that in the phenaceturates. On the other hand, N-alkylation of the side chain amide of malonamates, but not of phenaceturates, retains the susceptibility of the compounds to hydrolysis by beta-lactamases. This reactivity is not enhanced, however, by bridging the amide nitrogen and Calpha atoms. A phosphonate analogue of the malonamates was found to be an irreversible inhibitor of the beta-lactamases. These results, therefore, provide further evidence for the covalent access of compounds bearing retro-amide side chains to the active sites of beta-lactam-recognizing enzymes.

Accelerated esterification of aminoacids with lipoglycosylated α-chymotrypsin in polar solvents.

Abstract A lipodisaccharide possessing a reactive aldopentose function, the 6-O-octyl-β-D-galactopyranosyl-(l→5)-L-arabinose ( 5 ), has been prepared. The reductive alkylation of four of the lysine residues of the bovine α-chymotrypsin led to a lipo-1-deoxyglycytolated enzyme. This modified protein efficiently catalyzed the synthesis of N-acetyl aminoacid ethyl esters in different solvents with 2.5–3% water contents. Compared to the native enzyme, enhanced esterification rates were determined, particularly in tetrahydrofuran, ethyl acetate and acetonitrile.